X-25007290-G-C

Variant names:

• chrX-25007290-G-C
• NM_139058.3:c.1269C>G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_139058.3(ARX):​c.1269C>G​(p.His423Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000993 in 1,006,844 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 9.9e-7 (0 hom. 0 hem.)
• Consequence: ARX NM_139058.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.581

Genes affected

ARX (HGNC:18060): (aristaless related homeobox) This gene is a homeobox-containing gene expressed during development. The expressed protein contains two conserved domains, a C-peptide (or aristaless domain) and the prd-like class homeobox domain. It is a member of the group-II aristaless-related protein family whose members are expressed primarily in the central and/or peripheral nervous system. This gene is thought to be involved in CNS development. Expansion of a polyalanine tract and other mutations in this gene cause X-linked cognitive disability and epilepsy. [provided by RefSeq, Jul 2016]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARX	NM_139058.3	c.1269C>G	p.His423Gln	missense_variant	Exon 4 of 5	ENST00000379044.5	NP_620689.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ARX	ENST00000379044.5	c.1269C>G	p.His423Gln	missense_variant	Exon 4 of 5	1	NM_139058.3	ENSP00000368332.4
ARX	ENST00000637993.1	c.-121C>G		upstream_gene_variant		5		ENSP00000490122.1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome AF: 9.93e-7 AC: 1 AN: 1006844 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 320780

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000124

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 22

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.84
BayesDel_addAF	Uncertain	0.054	T
BayesDel_noAF	Benign	-0.16
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.46	T
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.63	T
M_CAP	Pathogenic	0.94	D
MetaRNN	Uncertain	0.45	T
MetaSVM	Uncertain	0.056	D
MutationAssessor	Benign	0.90	L
PrimateAI	Pathogenic	0.89	D
PROVEAN	Uncertain	-4.1	D
REVEL	Uncertain	0.49
Sift	Uncertain	0.026	D
Sift4G	Uncertain	0.025	D
Polyphen		1.0	D
Vest4		0.23
MutPred		0.24		Loss of catalytic residue at D427 (P = 0.1106);
MVP		0.94
MPC		1.2
ClinPred		0.99	D
GERP RS		-0.49
Varity_R		0.57
gMVP		0.92

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-25025407;